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J. Lipid Res.
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A more recent version of this article appeared on June 1, 2004

Papers In Press, published online ahead of print March 16, 2004
J. Lipid Res., doi:10.1194/jlr.M400007-JLR200
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Submitted on January 12, 2004
Revised on March 1, 2004
Accepted on March 3, 2004

The ATP-binding cassette transporter ABCA1 mediates lipid efflux from Sertoli cells and influences male fertility

David M. Selva, Veronica Hirsch-Reinshagen, Braydon Burgess, Steven Zhou, Jeniffer Chan, Sean McIsaac, Michael R. Hayden, Geoffrey L. Hammond, A. Wayne Vogl, and Cheryl L. Wellington

University of British Columbia, Vancouver, British Columbia V5Z 4H4

Corresponding Author: cheryl{at}cmmt.ubc.ca

The LXR/RXR regulated gene ABCA1 effluxes cellular cholesterol and phospholipid to apolipoprotein A1 (apoA1), which is the rate-limiting step in high-density lipoprotein synthesis. The RXR pathway plays a critical role in testicular lipid trafficking, and RXRb-deficient males are sterile and accumulate lipids in Sertoli cells. Here we demonstrate that ABCA1 mRNA and protein are abundant in Sertoli cells, whereas germ cells express little ABCA1. LXR/RXR agonists stimulate ABCA1 expression in cultured Sertoli MSC1 and Leydig TM3 cell lines. However, Sertoli TM4 cells lack ABCA1, and TM4 cells or primary Sertoli cells cultured from ABCA1-/- mice both fail to efflux cholesterol to apoA1. Expression of exogenous ABCA1 restores apoA1-dependent cholesterol efflux in Sertoli TM4 cells. In vivo, ABCA1-deficient mice exhibit lipid accumulation in Sertoli cells and depletion of normal lipid droplets from Leydig cells by 2 months of age. By 6 months of age, intratesticular testosterone levels and sperm counts are significantly reduced in ABCA1-/- mice compared to wild-type controls. Finally, a 21% decrease (p=0.01) in fertility was observed between ABCA1-/- males compared to wild-type controls across their reproductive lifespans. These results show that ABCA1 plays an important role in lipid transport in Sertoli cells and influences male fertility


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